Is NPHP4 p.Arg848Trp (c.2542C>T) pathogenic?

NPHP4 p.Arg848Trp (c.2542C>T) is classified Benign/Likely benign in NPHP4 (ClinVar, Multiple submitters, 14 submitters; last evaluated 2026-04-01). AlphaMissense: likely benign (0.126); Low-frequency (popmax 2.46%, nfe); Associated with kidney disorder.

What condition is associated with NPHP4 p.Arg848Trp (c.2542C>T)?

NPHP4 p.Arg848Trp (c.2542C>T) is associated with kidney disorder, nephronophthisis 4, nephronophthisis (ClinVar).

How common is NPHP4 p.Arg848Trp (c.2542C>T) in the general population?

NPHP4 p.Arg848Trp (c.2542C>T) is low-frequency (popmax 2.46%, nfe) (gnomAD).

What do computational predictors say about NPHP4 p.Arg848Trp (c.2542C>T)?

AlphaMissense predicts likely benign (score 0.126) — an in-silico prediction, not a clinical call.

NPHP4 p.Arg848Trp

c.2542C>T · rs17472401 · VCV95675

Benign/Likely benign Multiple submitters

Classification

Benign/Likely benign

ClinVar

Review

Multiple submitters ★★☆☆

ClinVar · 14 submitters

AlphaMissense

likely benign

0.126 · ACMG-weighted

gnomAD v4.1

Rare

low-frequency (popmax 2.46%, nfe)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

kidney disorder

Computational evidence

Protein change
AlphaMissense	0.126	likely benign
REVEL	0.476	indeterminate
SaProt	LLR -8.32	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.94	GERP -0.63, phastCons 0.002
Regional constraint	o/e 1.02	unconstrained · MANE · 123 kb · p 0.49 · regional, not allelic
Overall
CADD	22.5	PHRED · no single calibrated threshold — expert panels disagree

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 2.46% European (non-Finnish) · 29,072/1,179,712 alleles

Filtering AF 2.44% ClinGen BA1/BS1 input FAF95, joint · FAF99 2.43%

Overall 2.1% 33,913/1,613,640 alleles · low-frequency exomes 31,535/1,461,332 · genomes 2,378/152,308 · joint denominator

Ancestry group	Frequency	1 in
Amishnot grpmax-eligible	5.59%	18
Ashkenazi Jewishnot grpmax-eligible	2.77%	36
Finnishnot grpmax-eligible	2.5%	40
European (non-Finnish)grpmax	2.46%	41
Remaining individualsnot grpmax-eligible	1.93%	52
Middle Eastern	1.01%	99
Admixed American	0.552%	181
South Asian	0.502%	199
African / African-American	0.401%	249
East Asian	0.0334%	2,991

Amish shows a higher raw frequency than the grpmax group above it. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and “Remaining individuals” — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: NPHP4
Protein: p.Arg848Trp
Coding: c.2542C>T
MANE Select: NM_015102
dbSNP: rs17472401
Type: single nucleotide variant
Location: chr1:5880183 (GRCh38)
Gene constraint: LOEUF 1.183 · pLI <0.01 (gnomAD)
Structure: AlphaFold pLDDT 72.44
Residue 848: the 'sufficient for basal bodies localization' region; a UniProt-annotated variant site (does not affect interaction with rpgrip1l; does not affect interaction with rpgrip1)

Full NPHP4 gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

kidney disorder — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Also linked: nephronophthisis 4 nephronophthisis

Similar variants

NPHP4 p.Arg848Gln Uncertain significance ★★ ⚠ same residue
NPHP4 c.2304+1G>A Pathogenic ★★ same condition
NPHP4 c.2611+1G>A Pathogenic/Likely pathogenic ★★ same condition
NPHP4 c.2611+1G>C Pathogenic ★★ same condition
NPHP4 c.3644+1G>A Pathogenic/Likely pathogenic ★★ same condition
NPHP4 c.3644+1G>T Pathogenic/Likely pathogenic ★★ same condition
NPHP4 c.517+1G>A Pathogenic/Likely pathogenic ★★ same condition
NPHP4 c.518-2A>G Likely pathogenic ★★ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/nphp4-p-arg848trp (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown